EXCEED THE SPACE PROVIDED. |we now have established the feasibility or a sheep model system to investigate t AS and will exploit the unique .dvantages offered by this system in this renewal application. Fetal alcohol exposure (BACs of 260 mg/dl) iroduced brain cell loss but did not result in fetal hypoxemia. However, it is still possible that alcohol reduces ixygen delivery to the brain by altering blood flow. Specific aim #1 will test the hypothesis that fetal alcohol xposure decreases local brain blood flow and thus oxygen delivery without decreasing blood oxygen content by nfusing isotope-labeled microspheres into the circulation of chronicallyinstrumented fetal sheep to measure blood low in alcohol-sensitive brain regions. Also, alcohol exposure resulted in maternal hypoxemia and acidemia and etal acidemia without fetal hypoxemia. Specific aim #2 will test the hypothesis that repeated episodes of moderate acidemia mediate fetal brain injury by manipulating the maternal inspired gas concentrations to create maternal and etal blood gases like those mediated by alcohol exposure and relate this to neuron numbers in alcohol-sensitive brain regions. We found that alcohol acts on both sides of the placenta to stimulate.the hypothalamus pituitary adrenal axes. Specific aim #3 will test the hypothesis that elevations of fetal cortisol as a result of alcohol exposure >lay a role in mediating fetal brain injury. And finally, although FAS was identified almost 30 years ago, no studies lave yet explored the advantages to the conceptus of limiting heavy drinking to the first trimester. Specific aim #4 test the hypothesis that alcohol exposure limited to the first trimester will result in brain injury, but injury that differs quantitatively and qualitatively from that resulting from exposure during all three trimesters or exposure imited to the third trimester (the periods investigated during the previous funding period). In summary, we reason hat if alcohol induces cell loss indirectly, via acidemia, hypoxia or increases in fetal cortisol, then obtaining cell oss by manipulating these variables to a degree similar to that achieved by alcohol but independent of alcohol administration will mechanistically test.their roles in mediating brain injury. Together, these hypothesis-drive; studies that are practical only in an animal model system such as the sheep will answer important mechanism o damage, temporal and regional vulnerability questions and also will provide unique data that could be ve mportant in helping to persuade pregnant women to stop or reduce their drinking early in pregnancy.